A synthetic estrogen drug known as diethylstilbestrol (DES) was given to an estimated 3 million pregnant women in the 1940s through 1970s based on the belief that it would lower their risk of miscarriage and reduce pregnancy complications.

But in 1971, it was discovered that young women whose mothers took DES – “DES daughters” – were highly prone to aggressive vaginal cancers. Later research found that DES daughters are also at risk of infertility and abnormal pregnancies, and their children, DES grandchildren, have higher rates of genital-related birth defects and reproductive issues. These terrible effects arise because the drug – referred to as an endocrine disruptor – interferes with the natural steroid hormone signaling that mediates reproductive tissue development.

Now, a new investigation published in JAMA Pediatrics reveals the first evidence that DES grandchildren may also have neurological deficits with the finding that DES daughters are more likely to have children with attention-deficit/hyperactivity disorder (ADHD).

Using survey data from nearly 48,000 women followed as part of a long-term study, the authors determined that the rate of ADHD diagnosis was higher among children born to DES daughters compared with those born to women who were not exposed to DES in utero (7.7 vs 5.2 percent). Though this difference may seem small, a statistical analysis showed that it corresponded to a 63 percent greater risk of ADHD when the mother was exposed to DES during the first trimester of the grandmother’s pregnancy.

"While DES is banned, pregnant women continue to be exposed to a large number of environmental endocrine disruptors," senior author Marc Weisskopf said in a statement. "And although current exposures are at a lower level and potency than seen with DES, cumulative exposures to these chemicals may be cause for concern and is deserving of further study."

Exactly how DES impacts developmental outcomes multiple generations down the line remains unknown, yet the authors believe that epigenetic factors – changes in gene expression that don’t involve changing the underlying DNA sequences – may play a role.

“Although additional studies are warranted, these findings could suggest that the first trimester is a critical exposure window. The early phase of gestation is thought to be especially sensitive to maternal influences, resulting in embryonic and germ cell [epigenetic] reprogramming,” they wrote.

An emerging field of research suggests that just like mutations, epigenetic reprogramming caused by an environmental stressor – be it anxiety, famine, or disruptive chemicals – can be passed along via a theoretical phenomenon called transgenerational epigenetic inheritance. Whether or not DES has transgenerational effects, however, will not be clear until one more generation has been studied.

The children in this investigation are actually examples of direct exposure because the cells that would later become the DES daughters’ eggs were also exposed to the DES in utero.